Severe combined immune deficiency (SCID) may result from inherited deficiency of the enzyme
adenosine deaminase (ADA). Children with ADA-deficient SCID often die from infections in
infancy, unless treated with either a bone marrow transplant or with ongoing injections of
PEG-ADA (Adagen) enzyme replacement therapy. Successful BMT requires the availability of a
matched sibling donor for greatest success, and treatment using bone marrow from a less-well
matched donor may have a higher rate of complications. PEG-ADA may restore and sustain
immunity for many years, but is very expensive and requires injections 1-2 times per week on
an ongoing basis. This clinical trial is evaluating the efficacy and safety of an
alternative approach, by adding a normal copy of the human ADA gene into stem cells from the
bone marrow of patients with ADA-deficient SCID. Eligible patients with ADA-deficient SCID,
lacking a matched sibling donor, will be eligible if they meet entry criteria for adequate
organ function and absence of active infections and following the informed consent process.
Bone marrow will be collected from the back of the pelvis from the patients and processed in
the laboratory to isolate the stem cells and add the human ADA gene using a retroviral
vector. The patients will receive a moderate dosage of busulfan, a chemotherapy agent that
eliminates some of the bone marrow stem cells in the patient, to "make space" for the
gene-corrected stem cells to grow once they are given back by IV. Patients will be followed
for two years to assess the potentially beneficial effects of the procedure on the function
of their immune system and to assess possible side-effects. This gene transfer approach may
provide a better and safer alternative for treatment of patients with ADA-deficient SCID.

Clinical Details

Official title: MND-ADA Transduction Of CD34+ Cells From The Umbilical Cord Blood Of Infants Or The Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)

Detailed description:
The proposed study population is affected with adenosine deaminase-deficient severe combined
immune deficiency (ADA-SCID), an autosomal recessive congenital immune deficiency. The basis
of the proposed study (and product) is retroviral-mediated transduction of autologous, bone
marrow derived CD34+ hematopoietic progenitor cells with the MND-ADA retroviral vector in a
5 day cell processing period. Transduction is followed by infusion of the washed cells into
subjects not receiving enzyme replacement therapy with Polyethylene-conjugated ADA (PEG-ADA,
ADAGEN7) who have had their PEG-ADA injections discontinued, and have undergone bone marrow
cytoreductive therapy with a single non-ablative treatment course of Busulfan. The dose of
cells infused will be determined by the patient-to-patient variation of the number of
progenitors available from individual patients. Statistical analyses post-infusion will
help determine the dose-response of the number of cells infused to the level of engraftment
and resulting level of immune reconstitution. Following cellular infusion, a primary
clinical end-point will be the absolute numbers of T and B lymphocytes containing the
transduced ADA gene by quantitative, real-time PCR analyses. Measurement of blood
mononuclear cell ADA enzyme levels will be analyzed. Based on the degree of marking of
lymphocytes and of granulocytes, the selective advantage of lymphocytes may be gauged.
Subjects will be monitored for the development of clonal proliferation, under the 15 year
plan required by the FDA. One major aim of the study will be to see if subjects can remain
off PEG-ADA and maintain protective immunity from the population of transduced lymphocytes
arising from transduced progenitors. If sufficient gene-modified cells result, and PEG-ADA
enzyme replacement therapy can be permanently discontinued, the advantage of this
therapeutic approach may change the standard of care for these patients.

Eligibility

Minimum age: 1 Month.
Maximum age: 18 Years.
Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Children > 1. 0 months of age with a diagnosis of ADA-deficient SCID based on:

- A in addition to evidence of genetic mutations affecting the ADA gene as

determined by a CLIA certified laboratory and clinical evidence of combined
immunodeficiency based on lymphopenia (absolute lymphocyte counts <2SD of
age-matched control values) and hypogammaglobulinemia (<2SD of age-matched
control values) or lack of specific antibody response to vaccination. In
addition, for patients to be eligible under this criterion, they must
present with a clinical history indicating life-threatening illness
characterized by increased frequency and/or severity of infections
resulting in hospitalization and/or the administration of intravenous
antibiotics, for bacterial or opportunistic infection.

3. Written informed consent according to guidelines of the Committee on Clinical
Investigations (CCI) at Childrens Hospital Los Angeles (CHLA).

This study is also open to delayed/late onset ADA-deficient patients who fulfill the
criteria 1, 2. A, and 3 and who are not receiving PEG-ADA treatment after being invited to
discuss all alternative treatment options with a physician not connected with the
protocol.